The invention relates to chemical compositions and methods for using the compositions for cleaning and decontaminating dialyzers.
The medical industry and other industries utilize devices that are required to be cleaned and decontaminated. Cleaning is the removal of foreign material, including organic soil such as blood, feces, respiratory secretions, etc., from objects. It has been reported that failure to remove foreign material from a medical device such as an endoscope before a disinfection or sterilization process is likely to render the process ineffective. (Rutala, W A, APIC Guideline for Selection and Use of Disinfectants, Am J Infect Control, August 1996; Vol. 24,4:313-342). The presence of organic material or soil may contribute to the failure of disinfection by harboring embedded microbes and preventing the penetration of the germicide. Additionally, some disinfectants are inactivated by organic material (Martin, M A, Reichelderfer, M, APIC Guideline for Infection Prevention and Control in Flexible Endoscopy, Am J Infect Control, 1 994;22:19-38). Decontaminating is defined as the removal of hazardous or unwanted materials such as bacteria, mold spores or other pathogenic life forms and the like, with high-level disinfection and sterilization representing different levels of decontamination. High-level disinfection is a process that eliminates many or all pathogenic microorganisms, with the exception of bacterial spores, from inanimate objects. Sterilization is a process that completely eliminates or destroys all forms of microbial life, including fungal and bacterial spores.
High-level disinfection can be expected to destroy all microorganisms, with the exception of high numbers of bacterial spores. A Food and Drug Administration (FDA) regulatory requirement for high-level disinfectants is that they achieve 100% kill of 100,000 to 1,000,000 organisms of Mycobacterium tuberculosis in the presence of 2% horse serum in a quantitative tuberculocidal test. An additional FDA regulatory requirement for high-level disinfectants is that they must also achieve sterilization over a longer exposure time than the disinfection regimen time. Sterilization is tested with a sporicidal activity test utilizing spores of Bacillus subtilis. 
Common commercially available high-level disinfectants include glutaraldehyde solutions between 2.4-3.4%, which typically require activation with an alkaline buffer just prior to use. Also available are an acidic (pH 1.6-2.0) 7.5%w/v hydrogen peroxide (H2O2) solution (Sporox(copyright), Reckitt and Colman, Inc.) and an acidic (pH 1.87) mixture of 1.0% H2O2 plus 0.08% peracetic acid (PAA) (Peract(trademark) 20, Minntech Corp. or CidexPA(copyright), Johnson and Johnson). The minimum effective concentration of PAA for high-level disinfection at 25 minutes (min) and 20xc2x0 C. is 0.05% (500 ppm) (Peract(trademark)). The minimum effective concentration of H2O2 for high-level disinfection at 30 min and 20xc2x0 C. is 6.0% (Sporox(copyright)).
High-level disinfecting solutions are also typically designed for a reuse option, depending upon the medical device. For example, a glutaraldehyde high-level disinfecting solution for endoscope reprocessing may be reused for as long as 28-30 days, while kidney dialyzers are disinfected with single-use solutions.
Kidney dialyzers pose an additional problem in high level disinfecting in that the materials utilized require particular performance criteria of the cleaning and disinfection solutions. Types of dialyzers include: (1) coil, which incorporates a membrane in the form of a flattened tube wound around a central, rigid cylinder core, with a supporting mesh between adjacent portions of the membranes; (2) parallel plate, which incorporates a membrane in tubular or sheet form supported by plates in a sandwiched configuration; and (3) hollow-fiber, which incorporates the semipermeable membrane in the form of the walls of very small fibers having a microscopic channel running through them. Most parallel plate and hollow-fiber membranes are made from cellulose acetate, cellulose triacetate, regenerated cellulose, cuprophan or polysulfone.
The semipermeable membranes used in dialyzers have large areas and high porosities, and after use become coated with blood proteins and other organic and cellular material. Dialysis fibers are also often clotted with blood cells, proteins and other debris. As a result, the membrane of a used dialyzer has a reduced capacity for dialysis and is highly susceptible to microbial growth. Effective killing of microorganisms on such a used membrane for the purpose of reusing the dialyzer is difficult to accomplish without damaging the membrane.
When initially introduced, dialyzers were one-use devices. Since 1980, dialyzer reuse has risen dramatically in order to reduce the overall cost to the patient and the health care delivery system. Hemodialyzers, reprocessed in conformance with the Association for the Advancement of Medical Instrumentation (AAMI) specific guidelines and performance tests, have an average use number, that is, the number of times a particular hemodialyzer has been used in patient treatment. This number has been increasing over the years, from a United States average of 10 reuses in 1986 to 15 reuses in 1996. The cost benefits achieved by reprocessing are significant. For example, a new dialyzer costs about $20-30. With reprocessing, a dialyzer can be used between 5-20 times without substantial loss of efficacy. The cost of reprocessing is approximately $6.60-7.72 per unit, including reprocessing solutions. The cost per reuse for reprocessing solutions is $0.99-1.14 (average $1.08). The amortized dialyzer cost per reuse is $1.35-2.00, based upon an average reuse of 15 times. Additionally, the cost per reuse for dialyzer hazardous medical waste disposal is $0.50-0.55, reuse technician labor costs are $14/hr, and the associated labor cost of manual cleaning/dislodging clots is $0.23. Accordingly, with reprocessing, the dialyzer cost per treatment is conservatively less than about $10, as opposed to $30 if a new dialyzer were used for each treatment. A typical patient receives approximately 156 treatments per year. In 1998 in the United States alone there were approximately 280,000 patients on hemodialysis, and about 86% of hemodialysis centers have a dialyzer reuse program. Therefore, there are about 35,060,480 reuses in the United States (280,000xc3x970.86xc3x97(156xe2x88x92156/15)). The U.S. market for reprocessing solutions in 1998 is estimated to be $34.7-40.0 million.
In addition to cost savings with dialyzer reuse, there are health advantages. Researchers have determined that reused dialyzers significantly mitigate patients"" xe2x80x9cnew dialyzerxe2x80x9d symptoms as well as immune reactions that often occur. The inherent clinical advantage of reused dialyzers has been attributed to both the reduction in trace contaminants such as ethylene oxide sterilant, and to the masking of immune reaction sites located on the membrane surface by protein deposits.
Dialyzer reprocessing involves three basic steps: (1) cleaning, (2) dialysis efficacy confirmation, and (3) high-level disinfecting involving soak times long enough to achieve sterilization. The cleaning step involves removing residual blood, organic and cellular material from the blood side and removing dialysate from the dialysate side of the semipermeable membrane. A number of cleaning solutions are known, including sodium hypochlorite bleach, PAA and H2O2. Purified water has also been used for cleaning. The cleaning solution must be rinsed from the dialyzer, typically with water.
Sodium hypochlorite bleach at a concentration of 0.5-1.0%w/v for 3 min exposure is utilized for cleaning. However, significant decreases in patient urea and creatinine clearance have been observed with high-flux polysulfone (F80B) dialyzers reprocessed with formaldehyde and bleach (Murthy et. al., Effect of Formaldehyde/Bleach Reprocessing on In Vivo Performances of High-Efficiency Cellulose and High-Flux Polysulfone Dialyzers. J Am Soc Nephrol:464472, 1997). Also, Kaplan and colleagues observed up to 20 g blood protein and specifically 15 g albumin loss into the dialysate per treatment with bleach-reprocessed, high-flux polysutfone (F80) dialyzers. Elimination of bleach from the reprocessing protocol led to a significant increase in serum albumin levels (Kaplan et al., Dialysate Protein Losses With Bleach Processed Polysulfone Dialyzers. Kidney Int 47;573-578, 1995). It is believed that reprocessing certain polysulfone dialyzers with bleach somehow alters membrane structure. Loss of the usual immune protection achieved with reused dialyzers has been shown to occur when sodium hypochlorite, particularly at elevated concentrations, is used for reprocessing, resulting in complement activation and neutropenia restored to near original levels. The problems associated with utilizing bleach in the reprocessing protocol have widespread ramifications; in the United States as of 1996, 42% of all patients were utilizing high-flux dialysis and 78% of those were utilizing polysulfone dialyzer membranes. Finally, while not reported within the kidney dialysis industry, it is known that chlorine bleach solution has a tendency to form so-called haloforms with organic compounds. These compounds are considered to be carcinogenic and are therefore also hazardous from the health perspective. In this context, it was recently reported that dialysis patients had an increase in cancer of 15% as compared to the general population (The Lancet, 354, 93-99, 1999).
Dialyzers reprocessed with prior art acidic H2O2 solutions have a significant reduction in ultrafiltration rate, indicating the presence of hydrolytically resistive protein deposits resistant to removal by H2O2. In addition, while prior art H2O2 solutions are useful in that they react vigorously with hemoglobin, can be effective in dissolving some clots in dialyzer headers and blood channels, and can restore dialyzer fiber bundle volume in some cases, elevated concentrations of H2O2 can rapidly generate gaseous oxygen reaction products, as evidenced by the reported bursting of noncompliant membrane capillary fibers. Acidic PAA reacts similarly with protein deposits, as PAA contains an equilibrium mixture of H2O2, PAA and acetic acid. Thus, acidic PAA will not remove protein deposits but can be effective in dissolving some clots.
Lastly, water used in the reprocessing cleaning step is generally ineffective in removing protein deposits or bound clots, as is the case with formaldehyde and glutaraldehyde.
The use of citric acid in connection with the cleaning of dialysis machines has been disclosed in a number of patents. Tell et al., U.S. Pat. No. 4,690,772, discloses a sterilizing and cleaning solution comprising sodium chlorite, citric acid and a sodium bicarbonate buffer. U.S. Pat. No. 5,480,565 to Levin discloses a method for reprocessing dialyzer cartridges used with kidney dialysis machines. The method involves filling the blood and dialysate compartments of the dialyzer with an aqueous solution containing citric acid at a concentration of about 1.0-5.0%w/v and then subjecting the dialyzer to an elevated temperature above 90xc2x0 C. and below 100xc2x0 C. for a period of at least 15 h. It is known, however, that citric acid is incapable of removing bound protein deposits from polymer surfaces at these temperatures. Moreover, the sodium chlorite solutions in the ""772 patent have the capacity to crosslink proteins in surface deposits, making them even more resistant to removal. Also, the heat utilized in the ""565 patent will further denature proteins and possibly create more deposits, as well as deposits which are more resistant to removal.
The efficacy confirmation step for dialyzer reprocessing involves confirming that membrane integrity and performance is substantially equivalent to that of a new dialyzer. Specifically, with respect to membrane performance, when the measured fiber bundle volume (FBV) of the membrane drops by 20%, the dialyzer is no longer reused.
The disinfection step involves subjecting the dialyzer to high level disinfection with a process or chemical disinfecting agent. Chemical disinfecting agents such as formaldehyde, glutaraldehyde or an acidic equilibrium mixture of PAA, H2O2 and acetic acid are typically employed. In the United States in 1996, 36% of dialysis centers used formaldehyde, 54% used PAA, 7% used glutaraldehyde and 3% used heat to disinfect and sterilize. A commonly used glutaraldehyde solution is Diacide(copyright) (Gulfstream Corp.), a 26%w/v concentrate of acidic glutaraldehyde which is activated with alkali just prior to use and then diluted with water to a final concentration of 0.8%w/v. In 1998, the most commonly used PAA-based product was Renalin(copyright) Dialyzer Reprocessing Concentrate (Renal Systems Division, Minntech Corp.). Renalin(copyright) is a concentrated solution of acidic 4%w/v PAA and 24%w/v H2O2, designed to be diluted to a 3.5%w/v concentration in water, yielding a final concentration of about 0.14%w/v (1400 ppm) PAA and about 0.84%w/v (8400 ppm) H2O2. The minimum effective concentration of PAA to achieve either high level disinfection in a short time interval or sterilization over a longer soak period is 500 ppm.
Another PPA solution is described in Japanese patent JP 11076380A. An English translation of this patent discloses a cleaning and disinfecting composition consisting of an aqueous solution containing 3.5-6% hydrogen peroxide, 5-30% of an organic acid and 0.4-3.4% of an organic peracid in a weight ratio so that the sum of the acid and peracid to the peroxide is at least 1. The preferred organic acid is acetic acid. The method of cleaning and disinfecting comprises diluting the composition 20 to 100 fold with water. The composition may be used to clean the dialysis line of an artificial dialyzer through single step cleaning, allows easy removal of mass precipitation of calcium salts, and has high storage stability and high safety in handling. The Japanese patent does not explicitly reveal the solution pH; however, its reference to a solution having xe2x80x9chigh storage stabilityxe2x80x9d (which Test 1 indicates is either four or eight weeks storage in darkness at 36xc2x0 C.) would require a pH of substantially less than 5. It is thus essentially equivalent to other highly acidic PAA solutions such as Renalin(copyright).
The chemical disinfecting agent must be able to be rinsed out of the dialyzer to below toxic levels, with a rinse-out period established for the particular agent. Typically, for glutaraldehyde disinfectants, 1 liter of isotonic sterile saline is perfused through the dialyzer fibers prior to dialyzer use, with sterile purified water additionally used to rinse the dialysate chamber. Moreover, since the dialyzer is connected to the vascular system during use, any residual chemical entity which may be reversibly bound to the semipermeable membrane and which may desorb from the dialyzer following the rinse should be non-immunogenic, i.e., it should not provoke an immune response.
While some of the above solutions enjoy some commercial success, all have inherent problems which limit their use. The alkaline glutaraldehyde solutions have an appreciable noxious odor and a low vapor threshold for toxicity, and thus require the concomitant use of a ventilation system. Glutaraldehyde also cross-links proteins and thus likely further clogs previously uncleaned dialyzers and further limits solute transport through the dialyzer fibers. The current commercial acidic H2O2 and PAA solutions do not efficiently clean dialyzers and result in limited dialyzer re-use life.
One potential solution to the aforementioned problems with highly acidic H2O2 and PAA solutions is the invention disclosed in U.S. Pat. No. 5,827,542. The ""542 patent discloses a low odor, aqueous, quick acting, room temperature disinfecting and/or sterilizing solution that is non-corrosive to metals and elastomers used in medical instruments which are in need of sterilization and disinfection, having a pH within the range of from about 2.0 to about 6.0. The solution consists essentially of from about 1% to about 30% by weight of a peroxide and from about 1% to about 30% by weight of malonic acid, or salt form thereof, the solution being effective at room temperature to disinfect medical instruments within 30 min without corroding surfaces of the medical instruments. The ""542 patent also discloses that the amount of peroxide component and the amount of malonic acid or carboxylic acid component are balanced such that the pH will be within the range of about pH 2.0-6.0, preferably about pH 3.0-5.0. However, all six patent examples at or above pH 5.0 do not achieve sterilization. Also disclosed is the composition packaging, wherein the composition may be prepackaged in solution form, ideally in two packages, one the peroxide and one the organic acid component, to be mixed at the point of use. This packaging is described as enhancing freshness. However, due to the slow approach to equilibrium between peroxide, organic acid and peracid, the production of the disinfecting peracid will not take place with the thirty min disinfection time specified by the patent. Thus, premixing of a peroxide and an organic acid component in the ""542 patent is inoperative. Diluents such as alcohols can also be employed. While this invention discloses solutions with higher pH, up to pH 6.0, which are inherently much less corrosive to metals, it employs a high concentration of peracid generated from the combination of the peroxide and the malonic or other carboxylic acid. High peracid concentrations are known to be incompatible with medical device adhesives used to bond metal and plastic parts together. Solution compatibility tests with medical device adhesives were not disclosed, and claims for adhesive compatibility were also not made. An additional disadvantage of the ""542 invention is the potential toxicity of the high concentrations of disclosed peracids, despite the unsupported statement to the contrary. The ""542 invention did not disclose cleaning of medical devices such as kidney dialyzers.
Thus, it can be seen that there remains a need for a safe, practical, and efficient cleaning and high-level disinfecting and sterilizing composition and method for reprocessing kidney dialyzers.
The invention is directed to a composition for cleaning and decontaminating a dialyzer. The composition comprises a source of at least one per-compound oxidant and a buffer in amounts to provide the per-compound oxidant at a concentration and pH effective for cleaning and decontaminating the dialyzer. The composition has a pH between about 5-11. The per-compound oxidant may be at least one peracid or hydrogen peroxide (H2O2) and at least one peracid. In different embodiments, the H2O2 concentration may be in the range of about 1-50%w/v, about 3-20%w/v, or about 6.5-8%w/v. The peracid may be at a concentration in the range of about 0.0050-10.0%w/v. The per-compound oxidant may be a mixture of peracetic acid at about 0.0050-0.5%w/v and H2O2 at about 0.5-50.0%w/v or peracetic acid at about 0.005-0.2%w/v and H2O2 at about 0.5-8.0%w/v. The buffer may be acetic acid, propanoic acid, glycine, monobasic dihydrogen phosphate, dibasic hydrogen phosphate, bicarbonate, and/or carbonate, either with or without non-immunogenic counter ions.
The invention is also directed to a method of cleaning and decontaminating a dialyzer. A solution is produced by combining at least one per-compound oxidant and a buffer, mixed prior to use, in amounts to provide the per-compound oxidant at a concentration and pH effective for cleaning and decontaminating the dialyzer. The dialyzer is contacted with the solution for a period of time effective for cleaning and decontaminating. The method may included a further step of removing the solution from the dialyzer, for example, by rinsing with sterile water or sterile saline. The dialyzer may be stored to prevent recontamination. A soiled dialyzer may be treated to remove soil before it is contacted with the solution, for example, by contact with an enzyme solution.
The invention is also directed to a method of cleaning and decontaminating a dialyzer having a blood chamber and a dialysate chamber. At least one per-compound oxidant and a buffer are combined in amounts and at a pH effective to form a cleaning and decontaminating solution, then the blood chamber is contacted with the solution for a time effective for cleaning and decontaminating. The solution may also contact the dialysate chamber. The dialyzer may be vented to allow escape of a gas formed from combining the per-compound and buffer.
These and other objects and advantages of the present invention shall be made apparent from the accompanying description and examples.